In this specification where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not an admission that the document, act or item of knowledge or any combination thereof was at the priority date, publicly available, known to the public, part of common general knowledge; or known to be relevant to an attempt to solve any problem with which this specification is concerned.
The ability to effectively deliver therapeutic agents to animals and, in particular, humans is frequently dependent on compliance of the recipient. Compliance is also often connected or associated with the formulation used to deliver the agent. The formulations provided are also dependent on the ease of manufacture.
In addition, the formulation itself is often critical to the efficacy of the drug to be delivered. This is particularly the case for the delivery of pain relief agents such as paracetamol. One of the rate limiting steps in paracetamol delivery to the blood stream is the rate of gastric emptying. Various formulations which provide paracetamol at an alkaline pH have been proposed.
There is a continual need to develop more improved drug delivery formulations which efficaciously deliver therapeutic agents quickly yet without inducing unwanted side effects.
A major objective in drug delivery is to obtain a specific biological effect at a targeted site of action with minimal side effects. It is taught that bioactivity of a pharmaceutical will be sub-optimal if it does not possess the correct physiochemical properties to allow release of the biologically active form. For this reason improved drug delivery strategies focus on modifying physiochemical properties of active drugs including solubility, dissolution and dispersion.
Troches
Back in the 1800's, medical lozenges were extensively used to treat mouth and throat infections. These were small, square shape, mildly medicated solid masses intended to dissolve in the mouth. The finished troches are dispensed in plastic calibrated moulds that contain an accurate and precise dosage unit. In England they were called a lozenge, in the USA a troche, in France a tablette, and in Germany a pastillen. Troches slowly melt in the mouth and the active ingredients are absorbed mostly by the soft lining of the inner cheek. Here, blood vessels carry the hormones off to the rest of the body, similar to an injection with a needle.
Troches first appeared in the Edinburgh Pharmacopoeia in 1841 and then in 1864 in the British Pharmacopoeia. In the 1800s, troche making was an art way and required a lot of practical experience. The apparatus required to make troches was a smooth marble slab to mix them, a rolling pin, troche cutters, a palette knife, a badger brush with long soft hairs, linen cloth, and troche trays.
Today the computer has replaced the marble slabs, the wooden trays and brushes, etc. with complex electronic mixers, poly-glycol flavoured bases, accurate electronic scales (capable of measuring milligram doses) and miniature electric hot plates that make the finished troche an accurate and precise dosage form. The finished troches are dispensed in plastic calibrated moulds. The troches are available in a wide variety of flavours to assist compliance by even the fussiest patient.
The troches provide a means to deliver custom made medication in small doses directly into the blood stream. Today many drugs, both natural and synthetic, can be used in troche form to gain rapid onset of action and bypass the usual absorption into the blood stream, thus bypassing the liver. This reduces the load upon the liver and is especially good for liver toxic drugs.
Troches are currently used in hormone replacement therapy mainly because of the ease in which ingredients in each prescription can be altered and the buccal absorption does not involve gastric metabolism. Troches can also be mixed so that each individual troche contains a combination of various natural hormones in small doses. For example, a troche can be made containing a mixture of any of the bio-identical natural hormones, eg: estrogen, progesterone, testosterone and DHEA in any possible dosage. This combination is used to treat the symptoms of menopause. For male andropause, a combination of testosterone and DHEA is most commonly used. Troches containing natural progesterone alone are helpful for premenstrual syndrome and can be taken during the latter half of the menstrual cycle to alleviate depression, migraine, nausea and basically all those PMT symptoms that occur in the premenstrum.
They are also used for anaesthetics, antibiotics, analgesics, antimicrobials, antitussives, demulcents and other combinations of medicines.
Troches are being marketed as a method of administering agents that bypass the stomach and first pass metabolism of the liver as they are supposedly absorbed directly into buccal circulation. Claims are made that this places less stress on the liver and therefore is better for the patient. In reality, more than 50% (up to 70%) of the troche dose is actually swallowed by the normal salivation process which will encounter the stomach acids and first pass metabolism while the remainder is absorbed by the buccal mucosa (Int J Pharm Comp., 4, 414-420, 2000). With only 30 to 50% of the dose being absorbed through the mucosal lining in the mouth there appears to be only a minimal reduction in the livers first pass metabolism when compared to capsules. The hormones that are eventually absorbed, whether it is by the buccal mucosa or the gastrointestinal tract, will eventually encounter the liver anyway at some stage through normal circulation so there is no real significant liver sparing effect. Clinical experience shows that the doses required for troches are within the same range as those required for capsules so the overall “total load” on the body is approximately the same so again no real liver sparing benefit is obtained. Creams on the other hand require lower doses compared to troches and capsules and actually do bypass the stomach and first pass metabolism of the liver so are therefore the only way that actually reduces the overall load on the liver.
Hormones that possess poor oral bioavailability such as progesterone and testosterone (10 to 15% bioavailability) could potentially be good candidates for buccal administration. If successful the dosages for buccal administration should approach those of normal physiological doses e.g. progesterone 20 to 40 mg daily as found with creams. Clinical experience shows that the doses of progesterone needed in troches is usually between 200 to 400 mg daily which indicates a great deal of the dose is not being absorbed by the buccal mucosa thus supporting the evidence that a majority of the dose is being swallowed. Perhaps a buccal patch would provide better absorption characteristics than troches but are currently unavailable. In addition, there is no real benefit using buccal administration over oral administration for those hormones such as the estrogens and DHEA which already possess good oral bioavailability (over 90%).
Troches also exhibit poor pharmacokinetic parameters. This means that there are great fluctuations in hormone serum levels after taking a troche dose. Soon after taking a troche serum hormone levels rise rapidly, sometimes to very high levels, and then rapidly fall to low levels within 4 to 5 hours. They therefore require at least twice daily administration or for optimal results three to four times a day to maintain adequate levels longer however compliance becomes a major problem with this type of dosing schedule. This wide fluctuation in hormone levels is not the ideal situation. Creams and slow release capsules release hormones into the blood stream more gradually achieving steadier serum levels for a longer period of time thus generally requiring only once a day dosing.
Troches are made from two different types of bases both of which have several drawbacks:                polyethylene glycol (PEG)—PEG bases are well known to cause allergic and sensitivity reactions and can cause the buccal mucosa to become inflamed. In addition PEG's can contain small amounts of dioxin, an industrial solvent shown to cause cancer; and        gelatin—is a hydrophilic (water loving) base which causes hydrophobic (fat loving) particles such as bioidentical hormones to aggregate together. This aggregation of particles further reduces mucosal absorption thus increasing the amount swallowed and also does not allow for an even dispersion of the hormones throughout the slurry causing greater dose variation between each troche made.        
In conclusion troches are currently being widely used to administer bioidentical hormones to women however they possess many drawbacks and are not considered the optimal choice. Transdermal creams are considered the first choice by many as they require lower doses compared to troches and capsules and they are the only route of administration that truly bypasses the stomach and first pass metabolism. They provide better release parameters providing steady serum levels without wild fluctuations seen with troches. They only require once daily dosing so are more convenient, dosage adjustments are very easy to make and finally they are significantly cheaper with a standard formula costing about $30/month. If creams are deemed unsuitable in certain cases then the second choice should be slow release capsules. These capsules provide better release properties than troches, only require once a day dosing, and are fast to administer and no bitter taste. Troches are thought to be suitable for patients where creams are unsuitable and malabsorption syndrome occurs thus making oral administration unsuitable.
There is thus a need for improved formulations for sublingual or buccal delivery of agents to patients.
Bisphosphonates
One group of drugs which is particularly beneficial in a range of conditions are the bisphosphonates. Osteoporosis is one condition for which the bisphosphonate drugs, alendronate and risedronate, are frequently prescribed.
Osteoporosis and selected bone-resorptive conditions represent a significant medical disorder affecting millions of sufferers worldwide. Examples of other bone-resorptive conditions include other diseases or physiological states where there is an actual reduction or risk of reduction in bone mineral density and osteolysis from a normal reference range as a consequence of the disease or physiological state, such as menopause, hypogonadism, osteogenesis imperfecta, Paget's disease, myeloma bone disease, cancers metastatic to bone, primary hyperparathyroidism, fibrous dysplasia and hypercalcemia of malignancy.
For example, an estimated 44 million people in the United States over the age of 50 currently have either osteoporosis or low bone mass. This number could rise to over 61 million by 2020 (National Osteoporosis Foundation America's Bone Health: The State of Osteoporosis and Low Bone Mass, 2002).
Sufferers of osteoporosis face long-term drug therapy with anti-resorptive agents to prevent further bone loss. As indicated above, alendronate and risedronate are generally prescribed as anti-resorptive agents.
However, both agents are poorly absorbed (about 1% of the ingested dose), and this rate can be even lower if the drugs are not taken as directed. Non-compliance with current administration protocols is a common problem due to the gastrointestinal irritation of bisphosphonates which often leads to nausea and even vomiting in some subjects.
Bisphosphonates are also often prescribed in conjunction with hormone replacement therapy (HRT) to counter the effects of declining sex hormone production around the time of menopause. Sex hormone supplementation generally employs the gastrointestinal administration route, where significant amounts of hormone are degraded by the digestive environments encountered prior to absorption. As such, larger than required amounts of hormones must be used in the manufacture of oral hormone dosage forms to ensure a therapeutic dose reaches the circulation.
A number of HRT regimens specific for female menopausal symptoms have been devised, which have met with varying rates of clinical success. The majority of these treatments are based on the use of natural 17-β-oestradiol, conjugated equine oestrogen, or other conjugated oestrogens in combination with synthesised progestogens such as nor-ethisterone, levonorgestrel and dydrogesterone. Although such therapeutic combinations are highly successful in controlling symptoms, again patient compliance is often a limiting factor in their overall clinical efficiency. Side-effects such as gastrointestinal irritation and bloating are unacceptable to many patients.
Poor patient compliance is a significant barrier to the completion of prescription regimens and the cause of sub-optimal clinical outcome. There is thus a need to develop drug delivery formulations which reduce the side-effects that impact on patient compliance.